tbuckley/cabot-search huggingface dataset:
Variation of renal function in patients with urothelial carcinoma treated by tislelizumab-based immunochemotherapy.
Authors: Zhouliang Wu, Hailong Hu, Chong Shen, Houyuan Chen, Gangjian Zhao, Shiwang Huang, Kaipeng Jia, Yiduo Bai, Shizheng Guo, Zhe Zhang, Zhi Li, La Da, Yuda Lin
Journal: Journal of Clinical Oncology (2023)

494 Background: Treatment based on PD-1 ICIs brings advances to the treatment of urothelial carcinoma (UC). Although acute renal insufficiency is not common in iRAEs, the safety of immunotherapy in patients with renal impairment is still unknown. Consequently, we intend to investigate the effect of immunochemotherapy on nephritic function in the short term. Methods: Between July 2019 and September 2022, data of patients (pts) with UC that underwent tislelizumab based immunochemotherapy, including demographic information (age, gender), and creatinine level in baseline, after the first, second and third cycle (C1, C2 and C3) of immunotherapy in the Second Hospital of Tianjin medical University was collected and analyzed retrospectively. Estimated glomerular filtration rate (eGFR) is calculated according to CKD-EPI formula 2009, while pts were subdivided into different groups according to baseline eGFR, referencing to CKD categories in the K-DIGO 2012 guidelines for CKD classes. Data analyses were conducted using paired samples Wilcoxon Signed Rank Test and Kruskal-Wallis H test. Results: 163 pts have been included in our analyse totally. The median age was 67 years (IQR 61-74) and 128 (78.5%) were male. 135 (82%) pts received ICIs as perioperative treatment, while 19 (12%) pts were treated after radical operation. Metastasis is found in 9 (6%) pts before firstly received immunotherapy. Median creatinine (Cr) in baseline was 80.2umol/L (IQR 68.3-95.8), while median EGFR was 82.6 (IQR 64.3-93.8) mL/min/1. 73m 2 in all pts. According to CKD categories in the K-DIGO 2012 guidelines, at baseline, 57 pts are classified as G1 (eGFR≥90 mL/min/1.73m2), 74 pts as G2(eGFR &lt;90 mL/min/1.73 m 2 and≥60 mL/min/1.73 m 2 ), 30 as G3 (eGFR &lt;60 mL/min/1.73 m 2 and≥30 mL/min/1.73 m 2 ), and 2 as G4 (eGFR &lt;30 mL/min/1.73 m 2 and≥15 mL/min/1.73 m 2 ). No significant difference in eGFR between pts with CKD G1-2 in comparison to baseline and after the first (C1), second (C2) or third cycle(C3) of tislelizumab based immunotherapy (All p &gt;0.05). Notably, we found that eGFR improved in pts with CKD G3-4 when the first, second and third cycle completed, in comparison to the baseline.(p&lt;0.001, &lt;0.001, =0.002). Conclusions: Despite renal impairment is common in pts with UC, no evidence suggests that it is contraindicated for tislelizumab based treatment. More importantly, PD-1 immunotherapy may provide better nephritic benefits in patients with renal insufficiency. [Table: see text]
An oral androgen receptor RIPTAC for prostate cancer.
Authors: Kanak Raina, Kyle J Eastman, Xinheng Yu, Chris D Forbes, Kelli M Jones, James J Mousseau, Hao Li, Katherine J Kayser-Bricker, Craig M Crews
Journal: Journal of Clinical Oncology (2023)

184 Background: Resistance to Androgen Receptor Signaling Inhibitors (ARSIs) in prostate cancer occurs in almost all patients and is driven primarily by genomic alterations in AR and increases in AR expression. In the metastatic castration-resistant setting, more than 80% of these patients harbor amplifications of the AR gene or the upstream enhancer region of DNA. Our RIPTAC technology leverages the high level of AR expression to selectively kill prostate cancer cells while sparing normal tissues. Methods: We describe here a novel orally bioavailable heterobifunctional small molecule AR RIPTAC that recruits an essential cellular protein (EP) into a stable ternary complex with AR, thereby inhibiting EP function and leading to cell death selectively in AR-positive cells. Molecules were designed to achieve cooperative binding between AR and EP, oral bioavailability and AR-selective cell killing. Results: AR RIPTACs form a ternary complex between AR and EP across PCa cell lines with an EC 50 ~1nM, leading to concomitant inhibition of the EP and antiproliferative activity across PCa cell lines. The cell killing activity of AR RIPTACs is dependent on the presence of AR in the cell. AR RIPTACs induce apoptosis at low nM concentrations in cells overexpressing AR but not in control cells. In castrated mice bearing VCaP xenografts, AR RIPTACs accumulate in the tumor and induce AR:RIPTAC:EP ternary complex formation at a low oral dose, resulting in tumor specific inhibition of the EP and tumor growth inhibition. Leading AR RIPTACs possess pharmacokinetic properties suitable for a drug candidate, and readily achieve efficacious exposures following oral dosing in mouse, rat and dog. Conclusions: In summary, we report preclinical data on orally bioavailable heterobifunctional AR RIPTACs that are active in multiple prostate cancer models. The lead molecules are being evaluated in toxicology studies, with IND filing slated for 2024.
A phase 2 expansion study of ARV-766, a PROTACandrogen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniel P. Petrylak, Tyler F. Stewart, Xin Gao, Elmer Berghorn, Haolan Lu, Edward Chan, Richard Gedrich, Joshua Michael Lang, Meredith McKean
Journal: Journal of Clinical Oncology (2023)

TPS290 Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA 30 ) and 50% (PSA 50 ). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .
Single and multi-hit <i>PIK3CA</i> short variant (SV) genomic alterations (GA) in clinically advanced prostate cancer (CAPC): A genomic landscape study.
Authors: Carla Miguel, Gennady Bratslavsky, Joseph M Jacob, Petros Grivas, Philippe E. Spiess, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Ethan Sokol, Smruthy Sivakumar, Ryon Graf, Neil Vasan, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2023)

258 Background: Tumors harboring 2 or more PIK3CA Short variants (SV) (“Multi-hit”) have been described in breast cancer as linked to enhanced clinical outcome from anti-PIK3CA targeted therapies including alpelisib and investigational agents in clinical trials. The landscape and clinical implications of multi-hit PIK3CA alterations in other tumors, including in CAPC, are underexplored. Methods: 19,978 CAPC samples underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of GA and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, signature and loss of heterozygosity (gLOH). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 18,741 (93.8%) CAPC were PIK3CA wild type (WT), 1,155 (5.8%) featured a single PIK3CA SV and 82 (0.4%) featured multi-hit PIK3CA SVs. The median ages of CAPC patients with single hit (69.1 yrs) or multi-hit (68.7 yrs) PIK3CA SV were older than the PIK3CA WT (67.6 yrs) CAPC (p&lt;.0001 for both). At 14.0%, African ancestry was more frequent in PIK3CA WT CAPC than in single-hit (10.4%; p=.001) and multi-hit (10.2%; not significant). Single-hit (81.4%; p&lt;.0001) and multi-hit (85.2% p=.05) PIK3CA SV CAPC featured significantly more MMR trinucleotide genomic signatures than PIK3CA WT (64.8%). Single-hit (2.7%; p=.02) and multi-hit (5.8% p=.05) PIK3CA SV CAPC featured significantly more POLE trinucleotide genomic signatures than PIK3CA WT (0.4%). MSI high status was significantly more common in both PIK3CA single-hit (12.4% vs 2.5%; p&lt;.0001) and multi-hit (35.4% vs 2.5%; p&lt;.0001). Mean TMB was also significantly higher in single-hit PIK3CA (11.1 vs 3.5 mut/Mb; p&lt;.0001) and multi-hit (42.9 vs 3.5 mut/Mb; p&lt;.0001). Noteworthy differences in GA of potential importance for CAPC pts included significantly higher frequencies of GA in BRCA2 in multi-hit vs WT (18.3% vs 8.5%; p=.019), ATM in multi-hit vs WT (13.4% vs 5.6%; p=.02) and PTEN in single-hit vs WT (40.2% vs 30.1%; p&lt;.0001) and lower frequencies of GA in CDK12 (3.6% vs 5.6%; p=.009) and SPOP (7.4% vs 9.8%; p=.012) in single-hit vs WT. There were no differences in gLOH or PD-L1 expression among the 3 groups. Conclusions: Although uncommon, the identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique subtype of this disease that may be associated with enhanced responsiveness to anti-PIK3CA targeted therapy strategies.
Evaluation of ctDNA in patients with CRPC with pathogenic germline mutations in <i>BRCA2</i>.
Authors: Minqi Huang, Ellen B. Jaeger, Sydney Caputo, Crystal Casado, Albert Jang, Patrick L Sweeney, Sree M Lanka, Kanika Gupta, Alexandra Lieberman, Jennifer Schwartz, Olivia Pocha, Maddie Hawkins, Patrick Miller, Jodi Lyn Layton, Brian E. Lewis, Pedro C. Barata, Elisa M. Ledet, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

253 Background: Approximately 3-5% of advanced prostate cancer patients have pathogenic BRCA2 mutations in germline tests. In this study, we examine the relationship between pathogenic germline BRCA2 mutation and somatic changes in ctDNA. Methods: Germline screenings were performed by Invitae multi-cancer gene panel which includes 50-84 genes. ctDNA alterations were detected by Guardant 360 assays which report somatic changes in 70-83 genes. All ctDNA samples were collected in post-abiraterone and/or enzalutamide (in CRPC patients). Any pathogenic/likely pathogenic somatic alterations in the ctDNAs with more than 0.1% of allelic fraction were included in this cohort. The type of mutation detected in ctDNA was also assessed (truncating, point, etc.). Statistical significance for comparison is calculated with Fischer Exact Probablity Test and Chi-Square Test. Results: A total of 11 patients had germline BRCA2 pathogenic mutations and ctDNA assays; 267 patients had no germline DNA pathogenic alterations and ctDNA assays. Compared to germline normal patients, the germline BRCA2 mutations were less likely to have AR alterations on ctDNA (OR=0.2133, 95% C.I. [0.087, 0.525], p-value = 0.0003). BRCA2 germline positive patients were also more likely to have a mutated BRCA1, BRCA2, and TP53 ctDNA (OR=7.899, 95% C.I. [1.2745, 48.9548], p=0.055), (OR=7.899, 95% C.I. [1.7529, 16.059], p=0.008), and (OR=6.442, 95% C.I. [2.449, 16.946], p=0.00001), respectively. All other ctDNA assessed genes were mutated at a similar frequency between germline BRCA2 mutated and “normal” germline patients. BRCA2 germline mutations patients are less likely to have copy number alterations (CNVs) (OR=0.3992, 95% C.I. [0.2168, 0.7352], p=0.0031) and more likely to have frameshift mutations (OR=2.3182, 95% C.I. [1.169, 4.5972], p=0.0183). Conclusions: The ctDNA testing in this CRPC population (after abiraterone and/or enzalutamide) was less likely to find AR alterations and more likely to find pathogenic mutations for BRCA1, BRCA2, and TP53 in BRCA2 germline positive patients. In addition, BRCA2 germline positive CRPC patients were more likely to have frameshift mutations and less likely to have CNVs than those with an intact germline. Characterizing the mutational landscape in BRCA2 germline mutated patients may help to better define underlying disease biology. Those with BRCA mutated germline may be less likely to have AR driven tumors. More study is needed to better understand patients with underlying DNA repair defects.
Phase II trial evaluating olaparib maintenance in patients with metastatic castration resistant prostate cancer (mCRPC) after docetaxel treatment, reaching partial or stable response: SOGUG-IMANOL study.
Authors: Maria Jose Juan FITA, Urbano Anido Herranz, Maria Jose Mendez Vidal, Regina Gironés, Begoña Mellado-Gonzalez, José Manuel Sepulveda Sánchez, Carlos Alvarez-Fernandez, Miguel Ángel Climent, Lucia Heras
Journal: Journal of Clinical Oncology (2023)

168 Background: Prostate cancer is the second most common cancer in men. A number of important systemic therapies have been developed to treat mCRPC and now comprise the current therapeutic landscape. Docetaxel became the first systemic therapy to improve survival in these men in a randomized study demonstrating superiority versus mitoxantrone (18.9 months versus 16.5, p=0,004). But, inexorably, after stopping, disease progresses. Methods: A prospective phase II trial was designed to test Olaparib maintenance efficacy, in terms of progression free survival (PFS), in patients with mCRPC with DNA-repair defects that have achieved partial or complete response after being treated with systemic therapy (at least six cycles of docetaxel). Results: 134 mCRPC patients were included since Feb-2018 to Nov-2020 and were tested for DDR alterations. 19.4% of patients had somatic mutations (30.8% BRCA2, 3.8% BRCA1, 19.2% ATM, 7.7% CHEK2, 7.7% PALB2). 53,8% received Olaparib maintenance treatment, with a median follow-up of 23.3 months. Median age was 73 years. Median basal PSA was 17 ng/dL. 100% were metastatic (14.3% de novo and 85.7% relapsed after primary treatment), 78.6% had bone metastasis, 35.7% visceral and 35.7% adenopathies. 42.9% had previous treatment with abiraterone and 35.7% with enzalutamide. 46.2% received at least 8 cycles of docetaxel. 7.1% achieved a partial response and 92.9% a disease stabilization. Response to Olaparib treatment was 14.3% partial response, 71.4% stabilization and 7.1% disease progression.14.3% had a PSA50 decrease. Median duration of response was 8.27 months. Median PFS was 10.1 months. Median PSA-PFS was 3.5 months. G3/4 adverse events were 21.4% asthenia,14.3% anemia and 7.1% neutropenia. Conclusions: Olaparib maintenance after at least six cycles of docetaxel shows promising activity in mCRPC with DDR alterations, with an acceptable toxicity profile. Our pathogenic mutations percentage (19,4%) is in line with previous publications. Clinical trial information: NCT03434158 .
Sequential intravesical gemcitabine and docetaxel versus bacillus Calmette-Guérin for the treatment of high-risk, treatment-naïve, non-muscle invasive bladder cancer.
Authors: Ian M. McElree, Ryan L. Steinberg, Sarah L. Mott, Michael A. O'Donnell, Vignesh T. Packiam
Journal: Journal of Clinical Oncology (2023)

497 Background: Due to ongoing bacillus Calmette-Guerin (BCG) shortages, sequential intravesical gemcitabine and docetaxel (Gem/Doce) has been increasingly utilized as first-line adjuvant treatment for patients with high-risk non-muscle invasive bladder cancer. Herein, we compared oncologic outcomes and tolerance of Gem/Doce versus BCG. Methods: We retrospectively identified 312 patients with high-risk, treatment-naïve, NMIBC treated at our institution between January 2011 and December 2021; 174 treated with BCG and 138 treated with Gem/Doce. After complete TURBT, patients received a 6 weekly intravesical induction regimen of Gem/Doce or BCG, followed by maintenance if disease free at first follow-up. The primary outcome was high-grade (HG) recurrence-free survival (RFS). Cox multivariable regression analyses were performed. Adverse events were reported using CTCAE v5. Results: Median follow-up for patients receiving Gem/Doce and BCG was 23 and 49 months, respectively. Baseline clinicopathologic characteristics were similar between groups, including presence of CIS (41% vs 44%, p=0.6) and T1 (37% vs 41%, p=0.5) disease for patients receiving Gem/Doce and BCG, respectively. HG-RFS estimates at 6, 12, and 24-months were 92%, 85%, and 81% for Gem/Doce and 76%, 71%, and 69% for BCG, respectively. On multivariable Cox regression analyses controlling for age, gender, treatment year, and presence of CIS, Gem/Doce treatment was associated with superior HG-RFS (HR 0.57, p=0.04) and RFS (HR 0.56, p=0.02) versus BCG (Table). Progression-free, cystectomy-free, cancer-specific, and overall survival were similar between groups. Induction BCG was associated with greater treatment discontinuation (9.2% vs 2.9%, p=0.02), dysuria (p=0.03), and arthralgias (p=0.02), but less bladder spasms (p&lt;0.01) than Gem/Doce, respectively. Conclusions: In the setting of ongoing BCG production shortages, we found Gem/Doce to be an efficacious and well-tolerated alternative first-line therapy for high-risk NMIBC. Prospective randomized evaluation is being planned.
TRIUMPH: Phase II trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer harboring germline DNA repair gene mutations.
Authors: Mark Christopher Markowski, Cora N. Sternberg, Hao Wang, Rana Sullivan, Serina King, Tamara L. Lotan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2023)

190 Background: Androgen deprivation therapy (ADT) is the backbone of treatment for patients (pts) with metastatic prostate cancer (PCa), but many pts find this difficult to tolerate. Treatment with non-castrating regimens may avoid or delay the toxicities of hormonal therapy. The activity of PARP inhibitors (PARPi) in pts with homologous recombination DNA-repair (HRD) mutations (muts) and metastatic castration-resistant PCa has been established. We hypothesized here that the benefit of ARPi can be maintained in the absence of ADT in a biomarker-selected (HRD mutated) population with PCa. We designed a Phase 2 study in men with hormone-naïve, metastatic PCa who harbored a germline HRD mut treated with rucaparib monotherapy (without ADT). Methods: This was a multi-center, single arm Phase 2 study (NCT03413995) in men with asymptomatic hormone-sensitive metastatic PCa who received rucaparib 600mg by mouth daily. During consenting, pts were informed and had to opt out of ADT-based therapy. Pts must have had a germline mutation in an HRD gene on clinical-grade testing. The primary endpoint was confirmed PSA 50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 25% absolute increase in PSA 50 response from a null of 50%. Results: 12 pts were enrolled, 7 with BRCA1/2 and 5 with CHEK2 muts. The confirmed PSA 50 response rate to rucaparib was 41.7% (N=5/12, 95% CI: 19.3-68.1%), which did not meet the pre-specified efficacy boundary to enroll additional patients to 2 nd stage. In pts with measurable disease, the ORR was 60% (N=3/5, all with BRCA2). Median rPFS on rucaparib was 10.3 months (95% CI: 4.0 mo - NR). At the time of the interim analysis, 3 pts remained on study. The majority of adverse events (AE) were Grade ≤2 and expected. Translational studies are ongoing. Conclusions: Rucaparib can induce clinical responses in a biomarker-selected PCa population without concurrent ADT. However, the pre-specified threshold of PSA 50 response was not met. Although durable responses were observed in a subset of pts, PARPi without ADT in metastatic hormone sensitive PCa will not be pursued. Clinical trial information: NCT03413995 . [Table: see text]
Physician-driven artificial intelligence enabled planning for intraprostatic dose escalation in under ten minutes.
Authors: Kareem Rayn, Carl Elliston, Michelle Savacool, Yi Fang, Israel Deutsch, Catherine S. Spina, Lisa A. Kachnic, James B. Yu
Journal: Journal of Clinical Oncology (2023)

187 Background: Intraprostatic radiation dose escalation is an area of clinical interest. Dose escalation within the prostate must be balanced with maintaining acceptable dose to the organs at risk, OAR (bladder, rectum, and urethra). Treatment planning therefore requires simultaneous consideration of multiple competing plan optimization goals, for which iterative, interdisciplinary treatment planning tasks may take significant physician, physicist, and dosimetrist time. Semi-automated treatment planning using artificial intelligence has the potential to significantly reduce treatment planning time for technically complex treatments. Methods: A prostate SBRT planning template was created using the Varian ETHOS treatment planning system (TPS) combined with an in-house RapidPlan SBRT prostate model. Prostate dose was prescribed to 36.25 Gy over 5 fractions with 95% coverage to the PTV. To respect standard SBRT normal tissue toxicity constraints while simultaneously escalating intraprostatic dose, the TPS automatically created an intraprostatic boost structure (PTV_SIB), derived from the PTV by excluding OARs with a pre-determined margin. Physicians were trained to perform treatment planning using the prostate SBRT planning template. Treatment planning was performed on 5 unique patients. The time spent from initiation to end of treatment planning and dosimetric parameters were recorded. Results: For each patient, the ETHOS TPS generated two SBRT plans (9 field static IMRT and 3 VMAT arc) with intraprostatic dose escalation in an average of 9.3 minutes [range 8.4-11.8]. Static field and VMAT plans were comparable. PTV_SIB was escalated to above 50 Gy in all cases. Relevant dosimetry for each patient’s static IMRT plan is shown. Conclusions: Physician-driven ETHOS treatment planning was able to produce boosted internal PTV doses using autosegmented volumes. The ETHOS TPS was able to generate dose-escalated plans that reconciled complex OAR and PTV goals within 8-12 minutes. Hence, the ETHOS TPS opens the possibility of rapid physician-driven treatment planning throughput. [Table: see text]